According to the US National Cancer Institute, sulforaphane is considered to be one of the 40 most promising anticancer agents (Kelloff G. J, Crowell J. A, Steele V. E, Lubet R. A, Malone W. A, Boone C. W, Kopelovich L, Hawk E. T, Lieberman R, Lawrence J. A, Ali I, Viner J. L, Sigman C. C, J. Nutr, 2000, 130, 467). It is also known to possess antimicrobial properties. Sulforaphane has therefore attracted interest as a potential agent for the treatment and/or prevention of cancer and microbial infections.
Sulforaphane is found in the cruciferous vegetables such as cabbage, broccoli, broccoli sprouts, brussel sprouts, cauliflower, cauliflower sprouts, bok choy, kale, collards, arugula, kohlrabi, mustard, turnip, red raddish, and water cress. In the plant, it is present in bound form as glucoraphanin, a glucosinolate. In nature, sulforaphane is often formed from glucoraphanin following plant cell damage by an enzymatic reaction.
Various synthetic methods of producing sulforaphane are known in the art. Sulforaphane was synthesized as early as 1948 by Schmid and Karrer (Schmid H. And Karrer, P.; Helvetica Chimica Acta. 1948; 31; 6: 1497-1505). The Schmid synthesis results in a racemic mixture.
Various alternative synthetic procedures have been reported by, for example, Vermeulen and co-workers (Vermeulen M, Zwanenburg B, Chittenden G. J. F, Verhagen H, Eur. J. Med. Chem, 2003, 38(78), 729-737), Conaway and co-workers ((Conaway C. C, Wang C. X, Pittman B, Yang Y. M, Schwartz J. E, Tian D, McIntee E. J, Hecht S. S, Chung F. L, Cancer Research, 2005, 65(18), 8548-8557), Kuhnert and co-workers (Kuhnert N and Lu Y, Journal of Labelled Compounds & Radiopharmaceuticals 2004, 47(8), 501-507), Rajski and co-workers (Mays J. R and Rajski, S. R. Chem Bio Chem, 2008, 9(5), 729-747 and WO2008/008954), Christopher and co-workers (Christopher A. D'Souza, Shantu Amin, Dhimant Desai, Journal of Labelled Compounds & Radiopharmaceuticals, 2003, 46(9), 851-859), Takayuki and co-workers (Joon-Kwan M, Jun-Ran K, Young-Joon A and Takayuki S, Journal of Agricultural and Food Chemistry 2010, 58 (11), 6672-6677), and Rabhi and co-workers (WO 2008015315 and U.S. Pat. No. 0,135,618 A1), Cao and his co-workers (Tong Jian Ding, Ling Zhou, Xiao Ping Cao, Chinese Chemical Letters, 2006, 17(9), 1152-1154) and Chen and co-workers (Xin Chen, Zhengyi Li, Xiaoqiang Sun, Hongzhao Ma, Xiaoxin Chen, Jie Ren, Kun Hu, Synthesis, 2011, 24, 3991-3996 and CN 102249968).
Although sulforaphane has been synthesized by various different methods, most of the reported methods suffer several drawbacks; such as, for example, low yields, the use of hazardous and potentially harmful reagents (such as thiophosgene which is a highly toxic and volatile liquid with an unpleasant and irritating odour), the use of Class I or II solvents, laborious work-up/purification procedures and unwanted by-products (such as the inseparable disulfone/sulfonyl derivative of sulforaphane). These processes are therefore not suitable for the efficient large-scale synthesis of sulforaphane.
Therefore, there is a need for an alternative process for synthesising sulforaphane which address one or more of the aforementioned drawbacks of the prior art processes. In particular. There is a need for a synthetic process that can be implemented on a large scale. Such a process will ideally be:                (i) efficient, i.e. it gives commercially viable yields of sulforaphane with good levels of purity and utilises a small number of synthetic steps;        (ii) cost effective, i.e. utilising low cost reactants and reaction conditions;        (iii) environmentally acceptable and safe to implement, i.e. it does not use overly toxic reagents or solvents.        
One further and significant problem associated with sulforaphane is its inherent instability. Sulforaphane exists in the form of an unstable oil which rapidly degrades under normal conditions. This makes sulforaphane exceptionally hard to manufacture and distribute.
Therefore, there is also a need for a process of synthesising sulforaphane that is readily amenable to subsequent processing steps to provide a more stable form of the sulforaphane that is produced.
One particularly effective approach to stabilise sulforaphane involves the formation of sulforaphane-cyclodextrin complexes. In this regard, U.S. Pat. No. 7,879,822B2, the entire contents of which are hereby incorporated by reference, describes the preparation of sulforaphane-cyclodextrin complexes having good stability.
It therefore a further object of the present invention to provide a facile process that enables the sulforaphane that it synthesized to be readily stabilized by the formation of a sulforaphane-cyclodextrin complex.